What is the effect of rapamycin (Sirolimus) on neuroendocrine tumors?

Effect of Rapamycin (mTOR Inhibitors) on Neuroendocrine Tumors

Everolimus (an mTOR inhibitor closely related to rapamycin/sirolimus) significantly extends progression-free survival in advanced pancreatic neuroendocrine tumors and should be used as second-line therapy after somatostatin analog failure, while its role in non-pancreatic NETs remains less established. 1

FDA-Approved Indications for mTOR Inhibitors in NETs

• Everolimus is FDA-approved for progressive pancreatic NETs (pNETs) in patients with nonresectable, locally advanced, or metastatic disease, based on the RADIANT-3 trial demonstrating median PFS of 11 months versus 4.6 months with placebo (hazard ratio for disease progression significantly reduced by 6.4 months). 1, 2

• Sirolimus (rapamycin) itself is NOT FDA-approved for NET treatment, though everolimus and temsirolimus (both mTOR inhibitors) have established roles. 2

• Objective tumor response rates with everolimus remain modest at only 4.8% partial remissions, but disease control rate (partial response + stable disease) was substantially higher at 77.7% versus 52.7% with placebo. 1

Evidence-Based Treatment Algorithm by NET Type

Pancreatic NETs (Well-Differentiated, Progressive)

• First-line: Somatostatin analogs (octreotide LAR or lanreotide) for both functioning and non-functioning progressive G1/G2 tumors. 1, 3

• Second-line after SSA failure: Everolimus 10 mg once daily continuously is the standard based on RADIANT-3 trial results showing significant PFS benefit. 1

• Alternative second-line options: Sunitinib (PFS 11.1 vs 5.5 months with placebo), peptide receptor radionuclide therapy (PRRT) if somatostatin receptor-positive, or temozolomide-based chemotherapy. 1

Non-Pancreatic NETs (Carcinoid/Midgut)

• First-line: Somatostatin analogs remain the standard, with octreotide LAR demonstrating median time to progression of 14.3 months versus 6 months with placebo in the PROMID trial. 1, 3

• Everolimus role is less established: The RADIANT-2 trial in carcinoid patients showed median PFS of 16.4 months with everolimus plus octreotide versus 11.3 months with octreotide alone, but this did NOT meet the predefined threshold for statistical significance (p=0.026 but threshold not met). 1

• Current recommendation: Everolimus can be considered (category 3 recommendation) for progressive metastatic carcinoid tumors, particularly for symptom control in refractory carcinoid syndrome, though it is not FDA-approved for this indication. 1

Bronchial and Thymic NETs

• Limited but positive data: The RADIANT-2 trial included 44 of 429 patients with bronchial NETs, showing clear benefit of everolimus compared with placebo. 1

• Everolimus and sunitinib have been reported in very small series with mainly disease stabilization (objective response rates 5-10%). 1

Critical Adverse Effects and Monitoring

• Most frequently reported side effects with everolimus include stomatitis, anemia, hyperglycemia, rash, fatigue, and diarrhea; these are rarely grade 3 or 4. 1

• Increased risk of adverse events occurs in patients who previously received radiolabeled peptide therapy or chemotherapy. 1

• Monitoring requirements: Assess for stomatitis, metabolic parameters (glucose, lipids), complete blood counts, and renal function regularly during treatment. 1

Combination Therapy Considerations

Everolimus Plus Somatostatin Analogs

• RADIANT-1 trial data: Combination of everolimus with octreotide LAR showed significantly longer PFS (16.7 vs 9.7 months) compared to everolimus alone in progressive metastatic pancreatic NETs after chemotherapy failure. 1

• Mechanistic concern: Primary culture studies demonstrate that everolimus upregulates Akt activity through feedback loop relief, and SSAs do not overcome this Akt upregulation; furthermore, caspase-dependent apoptosis induced by SSAs was lost in combined treatments. 4

• Clinical practice: Despite mechanistic concerns, combination therapy is commonly used, particularly for symptom control in functional tumors. 1

Dual PI3K/mTOR Inhibition

• BEZ235 (dual PI3K/mTORC1/mTORC2 inhibitor) failed to demonstrate superiority over everolimus alone in a phase II trial (median PFS 8.2 months vs 10.8 months with everolimus) and showed poorer tolerability with 90.3% experiencing diarrhea. 5

Poorly Differentiated Neuroendocrine Carcinomas (Grade 3)

• High p-mTOR expression: 67% of poorly differentiated NECs show high p-mTOR expression, particularly all large cell neuroendocrine carcinomas, suggesting potential therapeutic role. 6

• Standard treatment remains chemotherapy: Cisplatin plus etoposide is standard for grade 3 NECs (response rate 42-67%, duration 8-9 months). 1

• mTOR inhibitors are NOT standard for grade 3 NECs, though high p-mTOR expression may suggest potential benefit in selected cases after chemotherapy failure. 6

Key Clinical Pitfalls to Avoid

• Do not use everolimus as first-line therapy in treatment-naïve patients with well-differentiated NETs; somatostatin analogs should be tried first given their favorable toxicity profile and proven efficacy. 1, 3

• Do not expect high objective response rates with everolimus; the primary benefit is disease stabilization and PFS prolongation, not tumor shrinkage. 1

• Do not use somatostatin analogs in grade 3 NECs regardless of site of origin, as they are not effective in this population. 1

• Do not assume sirolimus (rapamycin) has the same clinical evidence as everolimus; while mechanistically similar, everolimus has the robust clinical trial data and FDA approval for NETs. 2